Alzheimer's (AD) and other neurodegenerative diseases are characterized by extensive neuronal loss. However, the most commonly employed models of AD faithfully reproduce the amyloidogenic features of the disease but do not exhibit neuronal pathology and death, and most closely reflect early stages of AD. The primary goal of this application is to investigate the potential therapeutic efficacy of nuclear receptor agonists n the 5XFAD model that exhibits amyloid-driven neuronal pathology, death and behavioral deficits. These proofs of principal studies will establish if nuclear receptor agonists represent a effective treatment for individuals with diagnosed AD. In the brain, the nuclear receptors PPARs, LXRs and the NR4A receptors (Nurr1 and Nur77) form heterodimers with RXR and are activated by the RXR ligand, bexarotene. These receptors have three distinct types of actions: stimulation of metabolism, suppression of inflammation and a spectrum of actions on neurons that are broadly neuroprotective. A goal of this application is to determine the relative contributions of the individual heterodimeric nuclear receptors in ameliorating neuronal dysfunction and loss. We provide preliminary data demonstrating that the RXR agonist bexarotene stimulates the rapid clearance of both soluble forms of A? and amyloid plaques as well as the rapid reversal of behavioral deficits. Importantly, we show that one week of bexarotene treatment of 8 month old 5XFAD mice results in the near complete clearance of intraneuronal APP and A? peptides, coincident with a 70% reduction in plaque burden. The principal objective of this proposal is to ascertain which nuclear receptors mediate the salutary effects on neuronal dysfunction and death. This application has direct translational implications as phase II trials of bexarotene are being designed and are targeted to individuals at very early disease stages. The present study is particularly important as demonstrating drug efficacy on neuronal pathology and death will provide a rationale for treatment of AD patients at later disease stages. Aim 1:To examine the effect of nuclear receptor activation on neuronal dysfunction and death arising from amyloidogenesis. We will test the hypothesis that the neuronal dysfunction and death can be attenuated or prevented by the RXR agonist, bexarotene. Specifically, we will investigate if the clearance of intraneuronal APP/A? is correlated with the survival of these cells and if reduced levels of neuron loss are due to suppression of inflammation and enhancement of phagocytosis, or through other neuroprotective mechanisms. Aim 2. To determine if the NR4A class of nuclear receptors play critical roles in bexarotene-stimulated amelioration of AD pathogenesis. We propose to investigate the participation of the previously unappreciated targets of RXR action, the NR4A receptors in AD pathogenesis in the 5XFAD mice.